Compounds useful as motilin agonists and method

ABSTRACT

A method is provided for treating disorders of gastrointestinal motility which include the steps of administering to a patient in need of treatment of a compound having the structure  
                 
or a pharmaceutically acceptable salt thereof, a prodrug ester thereof, and all stereoisomers thereof,  
     wherein R 1  is selected from alkyl, aryl, cycloalkyl, alkenyl, alkynyl, arylalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl;  
     Z is selected from —CON(R 4 )R 4a , —SO 2 N(R 4 )R 4a , —CN, and  
                 
 
     R 4  and R 4a  are the same or different and are independently selected from hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl or R 4  and R 4a  can be joined together to form a heterocycle;  
     R 4b  is selected from hydrogen, halogen, hydroxyl, CN, OCF 3 , CF 3 , CONH 2 , SONH 2 , SO 2 CH 3 , NHCOCH 3  or NHCO 2 CH 3 ; and Q is a substituted bicyclic heterocycle. New compounds for use in treating disorders of gastrointestinal motility are also provided.

FIELD OF THE INVENTION

This application claims a benefit of priority from U.S. ProvisionalApplication No. 60/503,620, the entire disclosure of which is hereinincorporated by reference.

The present invention relates to novel compounds which are motilinagonists and to a method for using such compounds for the treatment ofgastrointestinal motility disorders.

BACKGROUND OF THE INVENTION

Gastrointestinal motility regulates the orderly movement of ingestedmaterial through the gut to insure adequate absorption of nutrients,electrolytes and fluids. Appropriate transit through the esophagus,stomach, small intestine and colon depends on regional control ofintraluminal pressure and several sphincters that regulate forwardmovement and prevent back-flow of gastrointestinal contents. The normalgastrointestinal motility pattern may be impaired by disease, surgery orby adverse reaction to drug treatment for non-gastrointestinal disease.

Motilin is a 22 amino acid peptide that is secreted fromenterochromaffin cells in the small intestine into the bloodstream,binds to a G-protein coupled receptor, GPR38, and is involved in thenormal regulation of coordinated motility of the gastrointestinal tract(J. C. Brown, M. A. Cook, J. R. Dryburgh; Can. J. Biochem., 1973,51:533). There is also evidence that the motilin receptor is expressedin the colon and motilin has been shown to increase cell calcium and tostimulate contraction of human colonic smooth muscle (G. Van Assche, I.Depoortere, T. Thijs, L. Missiaen, F. Pennenckx, H. Takashi, K. Geboes,J. Janssens, and T. L. Peeters, Neurogastroentero. Mot. 2001, 13:27-35).Erythromycin is a motilin agonist and is used therapeutically toincrease the rate of gastric emptying (T. Peeters, G. Matthijs, I.Depoortere, T. Cachet, J. Hoogmartens, G. Vantrappen, Am. J. Physiol.Gastrointest Liver Physiol., 1989, 257, G470-G474; J. Janssens, T. L.Peeters, G. Vantrappen, J. Tack, J. L. Urbain, M. DeRoo, E. Muls, R.Bouillon, N. Engl. J. Med. 1990, 1028-1031). In addition, motilinpeptide analogs and motilides have been shown to stimulate contractionin antral and colonic gastrointestinal muscle strips (L. Thielemans, I.Depoortere, J. V. Broeck, and T. L. Peeters, Biochem. Biophys. Res.Comm. 2002, 293, 1223-1227). Therefore, it is expected that potentmotilin agonists will act as a prokinetic agent and be useful for thetreatment of delayed gastric emptying (gastroparesis) in normal anddiabetic patients, postoperational ileus , irritable bowel syndrome,functional dyspepsia, chronic constipation, gastroesophogeal refluxdisease or other conditions where motility is delayed. It will also beuseful for treatment of colonic motility disorders including colonichypomotility. Moreover, motilin agonists will promote gastrointestinalmotility in a coordinated manner, thereby avoiding some common sideeffects associated with other prokinetic agents, such as nausea,constipation, and diarrhea.

Other examples of disorders whose symptoms include impairedgastrointestinal motility are anorexia, gall bladder stasis,postoperative paralytic ileus, scleroderma, intestinalpseudoobstruction, gastritis, emesis, and chronic constipation (colonicinertia). These gastrointestinal disorders are generally treated withprokinetic agents that enhance propulsive motility and thus could betreated with a motilin agonist.

U.S. Pat. No. 6,117,896 to Qabar et al. discloses β-sheet mimetics whichhave the structure

wherein

A is selected from —C(═O)—, —(CH₂)₀₋₄—, —C(═O)(CH₂)₁₋₃—, —(CH₂)₁₋₂₀— and—(CH₂ )₁₋₂S—;

B is selected from N and CH;

C is selected from —C(═O)—, —C(═O)(CH₂)₁₋₃—, —(CH₂)₀₋₃—, —O—, —S—,—O—(CH₂)₁₋₂— and —S(CH₂)₁₋₂—;

D is selected from N and C(R₄);

E is selected from

F is an optional carbonyl moiety;

R₁ and R₄ are independently selected from amino acid side chain moietiesand derivatives thereof;

R₂ and R₂′ represent one or more ring substituents individually selectedfrom an amino acid side chain moiety and derivatives thereof, or R₂taken together with C or Y forms a fused substituted or unsubstitutedhomocyclic or heterocyclic ring;

R₃ is selected from an amino acid side chain moiety and derivativesthereof, or taken together with C forms a bridging moiety selected from—(CH₂)₁₋₂—, —O— and —S—;

Y and Z represent the remainder of the molecule; and

any two adjacent CH groups of the bicyclic ring may form a double bond.

In one embodiment, R₂ taken together with C forms a heterocyclic fusedring as represented by

wherein A, B, C, D, E, R₂, R₂′, R₃ and Y are as defined above, and R′ isone or more optional ring substituents.

In one aspect of structure (X), R₂ and C taken together form a fusedfive-, six-, seven- or eight-membered ring as represented by structure(Xb):

wherein A, B, C, D, E, Y, R₂, R₂′, R₃ and R′ are as defined above, and Xis selected from —C(═O)—, —NH—, —NR′—, —O— and —S—.

SUMMARY OF THE INVENTION

In accordance with the present invention, a method is provided fortreating patients suffering from impaired gastrointestinal motility ordisorders involving gastrointestinal motility which includes the step ofadministering to a human patient, dog or cat in need thereof atherapeutically effective amount of a compound of the structure I as setbelow. Illustrative examples of disorders that may be treated with theinventive compounds include but are not limited to gastroparesis,gastroesophageal reflux disease, anorexia, gall bladder stasis,postoperative paralytic ileus, scleroderma, intestinalpseudoobstruction, gastritis, emesis, chronic constipation (colonicinertia), irritable bowel syndrome, functional dyspepsia, or otherconditions where motility is delayed as well as colonic motilitydisorders including colonic hypomotility.

The compounds useful in the above method include the compounds offormula I,

or a pharmaceutically acceptable salt thereof, a prodrug ester thereof,and all stereoisomers thereof;

wherein R₁ is selected from alkyl, aryl, cycloalkyl, alkenyl, alkynyl,arylalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl;

Z is selected from —CON(R₄)R_(4a), —SO₂N(R₄)R_(4a), CN, and

R₄ and R_(4a) are the same or different and are independently selectedfrom hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, orheteroarylalkyl or R₄ and R_(4a) can be joined together to form aheterocycle;

R_(4b) is selected from hydrogen, halogen, hydroxyl, CN, OCF₃, CF₃,CONH₂, SONH₂, SO₂CH₃, NHCOCH₃ or NHCO₂CH₃;

Q is a substituted bicyclic heterocycle selected from

wherein r is 0, 1 or 2 preferably as 1; and

represents a single bond or a double bond; and

T is selected from alkyl, aryl, cycloalkyl, alkenyl, alkynyl, arylalkyl,heteroaryl, heteroarylalkyl or heterocycloalkyl, and where each of thesegroups may be optionally substituted with R₅, R_(5a) and R_(5b);

R₅, R_(5a) and R_(5b) are the same or different and are independentlyselected from hydrogen, halogen, hydroxyl, OCF₃, CF₃, CN,NR_(5c)(R_(5d)), C(O)NR_(5c)(R_(5d)), OC(O)NR_(5c)(R_(5d)), OR_(5c),SO₂R_(5c), SO₂N(R_(5c))R_(5d), alkyl, alkoxyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl or heterocycloalkyl. Further, R₅ and R_(5a)can be joined together with —OCH₂O— or —OCH₂CH₂O— to form a fusedbicyclic ring with aryl or heteroaryl group;

R_(5c) and R_(5d) are the same or different and are independentlyselected from hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, or heterocycloalkyl or R_(5c) and R_(5d) can be joinedtogether to form a heterocycle.

Preferred compounds for use in the method of the invention are

These compounds (a), (b) and (c) are novel compounds and form part ofthe present invention as well.

DETAILED DESCRIPTION OF THE INVENTION

The following abbreviations are employed herein:

-   Boc=tert-butoxycarbonyl-   Boc₂O=di-tert-butyldicarbonate-   Cbz=benzyloxycarbonyl (or carbobenzoxy)-   Conc. HCl=concentrated aqueous hydrochloride-   DIEA or DIPEA=diisopropylethylamine-   DMAP=4-(dimethylamino)pyridine-   DMF=N,N-dimethylformamide-   EDAC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-   EtOAc=ethyl acetate-   HOAT or HOAt=1-hydroxy-7-azabenzotriazole-   HOBT=1-hydroxybenztriazole-   HPLC or LC=high performance liquid chromatography-   LC/MS=high performance liquid chromatography/mass spectrometry-   MS or Mass Spec=mass spectrometry-   NaOH=sodium hydroxide-   Na₂SO₄=sodium sulfate-   Pd/C=palladium on activated charcoal-   PyAOP=7-(azabenzotriazole-1-yloxy)tripyrrolidino-phosphonium-   hexafluorophosphate-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   YMC=trademark of YMC Co, Ltd., Kyoto, Japan-   g=gram(s)-   h or hr=hour(s)-   min=minute(s)-   ml=milliliter-   mg=milligram(s)-   mol=moles-   mmol=millimole(s)-   nM=nanomolar-   RT=room temperature-   Rt=HPLC or LC retention time-   Et=ethyl-   i-Pr=isopropyl-   Me=methyl

The following definitions apply to the terms as used throughout thisspecification, unless otherwise limited in specific instances.

Unless otherwise indicated, the term “alkyl” as employed herein alone oras part of another group includes both straight and branched chainhydrocarbons, containing 1 to 40 carbons, preferably 1 to 20 carbons,more preferably 1 to 6 carbons, in the normal chain, such as methyl,ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl,isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl,nonyl, decyl, undecyl, dodecyl, the various branched chain isomersthereof, and the like. Further, alkyl groups, as defined herein, mayoptionally be substituted on any available carbon atom with one to threefunctional groups (which may be the same or different) commonly attachedto such chains, such as, but not limited to alkyl, aryl, alkenyl,alkynyl, hydroxy, arylalkyl, cycloalkyl, cycloalkylalkyl, alkoxy,arylalkyloxy, alkanoyl, amino, halo, thio, cyano, carboxyl, carbonyl

amino, aminocarbonyl, alkoxylcarbonyl, amido, haloaryl, CF₃, OCF₃,aryloxy, heteroaryl, cycloalkylalkoxyalkyl, cycloheteroalkyl and thelike to form alkyl groups such as trifluoro methyl, 3-hydroxyhexyl,2-carboxypropyl, 2-fluoroethyl, carboxymethyl, cyanobutyl and the like.

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone or as part of another group includes saturated or partiallyunsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groupscontaining 1 to 3 rings, including monocyclic alkyl, bicyclic alkyl andtricyclic alkyl, containing a total of 3 to 20 carbons forming therings, preferably 4 to 12 carbons, forming the ring, and which may befused to 1 aromatic ring as described for aryl, which includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl,

any of which groups may be optionally substituted with 1 to 3substituents as defined above for alkyl.

Unless otherwise indicated, the term “aryl”, as employed herein alone oras part of another group refers to monocyclic and bicyclic aromaticgroups containing 6 to 10 carbons in the ring portion (such as phenyl ornaphthyl including 1-naphthyl and 2-naphthyl) and may optionally includeone to three additional rings fused to a carbocyclic ring or aheterocyclic ring (such as aryl, cycloalkyl, heteroaryl orcycloheteroalkyl rings for example

and may be optionally substituted through available carbon atoms with 1,2, or 3 groups selected from hydrogen, halo, alkyl, alkoxy, alkenyl,trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkyl,heterocyclicalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl,arylalkoxy, and/or any of the substituents for alkyl set out herein.

The term “arylalkyl” as used herein alone or as part of another grouprefers to alkyl grups as defined above having an aryl substituent suchas benzyl, phenethyl or naphthylpropyl, wherein said aryl and/or alkylgroups may optionally be substituted as defined above.

The term “alkoxy” or “aryloxy” as employed herein alone or as part ofanother group includes an alkyl or aryl group as defined above linkedthrough an oxygen atom.

Unless otherwise indicated, the term “alkenyl” as used herein by itselfor as part of another group refers to straight or branched chainradicals of 2 to 20 carbons, preferably 3 to 12 carbons, and morepreferably 2 to 6 carbons in the normal chain, which include one or moredouble bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl,2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl,3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl,4-dodecenyl, 4,8,12-tetradecatrienyl, and the like, and which may beoptionally substituted with one or more functional groups as definedabove for alkyl.

Unless otherwise indicated, the term “alkynyl” as used herein by itselfor as part of another group refers to straight or branched chainradicals of 2 to 20 carbons, preferably 2 to 12 carbons and morepreferably 2 to 8 carbons in the normal chain, which include one or moretriple bonds in the normal chain, such as 2-propynyl, 3-butynyl,2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl,3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl,3-undecynyl,4-dodecynyl and the like, and which may be optionally substituted withone or more functional groups as defined above for alkyl.

Unless otherwise indicated, the term “acyl” as employed herein by itselfor part of another group, as defined herein, refers to an organicradical linked to a carbonyl

group; examples of acyl groups include any of the R groups attached to acarbonyl, such as alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaroyl,cycloalkanoyl, cycloheteroalkanoyl and the like.

Unless otherwise indicated, the term “heterocycloalkyl” or“cycloheteroalkyl” as used herein alone or as part of another grouprefers to a 4-, 5-, 6- or 7-membered saturated or partially unsaturatedring which includes 1 to 3 hetero atoms such as nitrogen, oxygen andiorsuifur, iiiiked thiough a carbon atom or a heteroatom, such as

and the like. The above groups may include 1 to 4 substituents such asalkyl, halo, oxo and/or any of of the substituents for alkyl or aryl setout herein. In addition, any of the heterocycloalkyl rings can be fusedto a cycloalkyl, aryl, heteroaryl or heterocycloalkyl ring.

Unless otherwise indicated, the term “heteroaryl” as used herein aloneor as part of another group refers to a 5-, 6- or 7- membered aromaticring which includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygenor sulfur, SO or SO₂, and such rings fused to an aryl, cycloalkyl,heteroaryl or cycloheteroalkyl ring (e.g. benzothiophenyl, indolyl), andincludes possible N-oxides, linked through a carbon atom or aheteroatom. The heteroaryl group may optionally include 1 to 4substituents such as any of the substituents for alkyl or aryl set outabove. Examples of heteroaryl groups include the following:

and the like.

The term “heteroarylalkyl” as used herein alone or as part of anothergroup refers to a heteroaryl linked through an alkyl group.

The term “heterocyclo”, “heterocycle” or “heterocyclic”, as used herein,represents an unsubstituted or substituted stable 4-, 5-, 6- or7-membered monocyclic ring system which may be saturated or unsaturated,and which consists of carbon atoms and from one to four heteroatomsselected from N, O, S and or a SO or SO₂ group, wherein the nitrogen andsulfur heteroatoms may optionally be oxidized, and the nitrogenheteroatom may optionally be quaternized. The heterocyclic ring may beattached at any heteroatom or carbon atom which results in the creationof a stable structure. Examples of such heterocyclic groups include, butis not limited to, piperidinyl, piperazinyl, oxopiperazinyl,oxopiperidinyl and oxadiazolyl, as well as any of the heteroaryl groupsand cycloheteroalkyl groups set out above. Optionally a heterocyclogroup may be substituted with one or more functional groups, such asthose described for alkyl.

The term “alkoxyalkyl” or “aryloxyalkyl” as used herein alone or as partof another group refers to a alkoxy or aryloxy group respectively,linked through an alkyl group.

Any compound that can be converted in vivo to provide the bioactiveagent (i.e., the compound of formula I) is a prodrug within the scopeand spirit of the invention.

Various forms of prodrugs are well known in the art and are describedin:

The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch 31,(Academic Press, 1996);

Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); and

A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H.Bundgaard, eds. Ch 5, pgs 113-191 (Harwood Academic Publishers, 1991).

The compounds of the present invention all have at least two asymmetriccenters as noted by the asterisks in formula I. Additional asymmetriccenters may be present on the molecule depending upon the nature of thevarious substituents on the molecule. Each such asymmetric center willproduce two optical isomers and it is intended that all such opticalisomers, as separated, pure or partially purified optical isomers orracemic mixtures thereof, be included within the ambit of the instantinvention. One isomer might be slightly preferred in some cases, butboth are claimed. The racemic mixtures may be separated into individualoptical isomers employing conventional procedures such as bychromatography or fractional crystallization.

The pharmaceutically acceptable salts of the compounds of formula I ofthe invention include alkali metal salts such as lithium, sodium orpotassium, alkaline earth metal salts such as calcium or magnesium, aswell as zinc or aluminum and other cations such as ammonium, choline,diethanolamine, ethylenediamine, t-butylamine, t-octylamine,dehydroabietylamine, as well as pharmaceutically acceptable anions suchas chloride, bromide, iodide, tartrate, acetate, methanesulfonate,maleate, succinate, glutarate, and salts of naturally occurring aminoacids such as arginine, lysine, alanine and the like, and prodrug estersthereof.

General Synthetic Schemes

The compounds of the present invention may be prepared according to thefollowing general synthetic reaction schemes as well as relevantpublished literature procedures that may be used by one skilled in theart. Exemplary reagents, procedures and conditions for these reactionsappear hereinafter and in the working examples. Starting materials arecommercially available or can be readily prepared by one of ordinaryskill in the art using known methods. Unless otherwise specified thevarious substituents of the compounds are defined in the same manner asthe formula I compounds. During the preparation of compounds of formulaI, one or more protecting groups might be used, reaction conditions forprotection and deprotection may be found in the “Protective Groups inOrganic Synthesis” Greene et al., John Wiley and Sons Inc, 1999, orother methods used by one of ordinary skill in the art.

Scheme I describes a general synthetic sequence for the preparation ofthe compounds of formula I of the invention. Compounds of formula IV canbe prepared from carboxylic acids II and amines III using an appropriatecarboxylic acid activating reagent in an inert solvent. The abovereaction is carried out employing a molar ratio of II:III within therange from about 3:1 to about 0.3:1, preferably from about 1.2:1 toabout 0.8:1, at a temperature within the range from about −20 to about50° C., preferably from about 20 to about 30° C. Exemplary carboxylicacid activating agents include isobutylchloroformate,carbonyldiimidazole, dicyclohexylcarbodiimide, pentafluorophenoltrifluoroacetate, 7-(azabenzotriazole-1-yloxy)tripyrrolidino-phosphoniumhexafluorophosphate or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.Exemplary inert solvents include methylene chloride, tetrahydrofuran,N,N-dimethylformamide, ethers, dioxane, or acetonitrile. The abovereaction can also be carried by other methods described in Bodanszky, M.and Bodanszky, A. The Practice of Peptide Synthesis 1994,Springer-Verlag Berlin Heidelberg, New York, N.Y.

In some cases, there is an amine-protecting group (PG), such as Boc, CBZor Trityl in the Q moiety of compound IV. The protecting group may beremoved to afford the final compounds of formula I. Exemplarydeprotection reagents for Boc are hydrogen chloride in dioxane or TFA indichloromethane. Exemplary deprotection for CBZ is catalytichydrogenation or trimethylsilyl iodide in methylene chloride. Exemplarydeprotection for Trityl is hydrogen chloride in acetone ortetrahydrofuran. Additional conditions for deprotection may be founds inthe “Protective Groups in Organic Synthesis” Greene et al., John Wileyand Sons Inc, 1999, or other methods used by one of ordinary skill inthe art. Amines III including peptide amides or peptide mimics can beprepared by methods used by one of ordinary skill in the art.

Scheme II describes a general synthetic sequence for the preparation ofthe compounds of formula IX, a set of compounds employed in the methodof the invention. Compounds of formula VII can be prepared from atriazolidinedione V and pentadienoic ester VI in a two-step sequence.Treatment of triazolidinedione V with an oxidant such asbis(triacetoxy)iodobenzene or bis(trifluoroacetoxy)-iodobenzene givestriazoledione in situ, which is then allowed to react with pentadienoicester VI via a [4+2] cycloaddition to give compounds of formula VII. Theabove reaction is carried out employing a molar ratio of V:VI within therange from about 5:1 to about 1:1, preferably from about 1.5:1 to about1:1, at a temperature within the range from about −20 to about 50° C.,preferably from about 0 to about 25° C.

Basic hydrolysis of compounds VII using aqueous sodium hydroxide orlithium hydroxide provides unsaturated compounds of formula VIII.

Hydrogenation of compounds VII followed by basic hydrolysis alsoprovides saturated compounds of formula VIII.

Alternatively, hydrogenation can be accomplished after the basichydrolysis to give saturated compounds of formula VIII. Compound IX canbe prepared from compounds VIII and amines III in a similar manneraccording to the conditions described in Scheme I.

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of formula I, alone orin combination with a pharmaceutical carrier or diluent. Optionally,compounds of the present invention can be used alone, in combinationwith other compounds of the invention, or in combination with one ormore other therapeutic agent(s) or other pharmaceutically activematerials.

The compounds of the present invention may be employed in combinationwith other motilin agonists or other suitable therapeutic agents usefulin the treatment of the aforementioned disorders including agents totreat gastrointestinal disorders such as proton pump inhibitors, forexample, esomeprazole, lansoprazole or omeprazole; histamine H2 receptorblockers, for example, nizatidine, famotidine, cimetidine, orranitidine; antiacid agents such as aluminum antacids, calcium antacids,and magnesium antacids, and combinations as listed in the Physicians'Desk Reference (PDR); gastrointestinal stimulants, for example,metoclopramide; dopamine receptor blockers, for example, domperidone,fenoldapam mesylate, cabergoline, pramipexole, pergolide mesylate,ropinirole and amanitidine HCl; 5-HT4 agonists, for example, tegaserod(Zelnorm®) and 5-HT3 antagonists, for example, alosetron, as well asagents for treating anorexia, gall bladder stasis, agents for treatingpostoperative paralytic ileus, agents for treating scleroderma, agentsfor treating intestinal pseudo-obstruction, anti-gastritis agents,anti-emesis agents, anti-constipation agents for treating irritablebowel syndrome, agents for treating functional dyspepsia, and agents fortreating colonic hypomotility. The listing of the above agents includethose agents disclosed in the PDR.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the PDR or as otherwise determined by one ofordinary skill in the art.

The compounds of the formula I can be administered for any of the usesdescribed herein by any suitable means, for example, orally, such as inthe form of tablets, capsules, granules or powders; sublingually;bucally; parenterally, such as by subcutaneous, intravenous,intramuscular, or intrasternal injection or infusion techniques (e.g.,as sterile injectable aqueous or non-aqueous solutions or suspensions);nasally, including administration to the nasal membranes, such as byinhalation spray; topically, such as in the form of a cream or ointment;or rectally such as in the form of suppositories; in dosage unitformulations containing non-toxic, pharmaceutically acceptable vehiclesor diluents. The present compounds can, for example, be administered ina form suitable for immediate release or extended release. Immediaterelease or extended release can be achieved by the use of suitablepharmaceutical compositions comprising the present compounds, or,particularly in the case of extended release, by the use of devices suchas subcutaneous implants or osmotic pumps. The present compounds canalso be administered liposomally.

Exemplary compositions for oral administration include suspensions whichcan contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which can contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The compounds of formula I can also be delivered through theoral cavity by sublingual and/or buccal administration. Molded tablets,compressed tablets or freeze-dried tablets are exemplary forms which maybe used. Exemplary compositions include those formulating the presentcompound(s) with fast dissolving diluents such as mannitol, lactose,sucrose and/or cyclodextrins. Also included in such formulations may behigh molecular weight excipients such as celluloses (avicel) orpolyethylene glycols (PEG). Such formulations can also include anexcipient to aid mucosal adhesion such as hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose(SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents tocontrol release such as polyacrylic copolymer (e.g. Carbopol 934).Lubricants, glidants, flavors, coloring agents and stabilizers may alsobe added for ease of fabrication and use.

Exemplary compositions for nasal, aerosol, or inhalation administrationinclude solutions in saline which can contain, for example, benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, and/or other solubilizing or dispersing agents such asthose known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which can contain, for example, suitablenon-toxic, parenterally acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodiumchloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid, or Cremaphor.

Exemplary compositions for rectal administration include suppositorieswhich can contain, for example, a suitable non-irritating excipient,such as cocoa butter, synthetic glyceride esters or polyethyleneglycols, which are solid at ordinary temperatures, but liquefy and/ordissolve in the rectal cavity to release the drug.

Exemplary compositions for topical administration include a topicalcarrier such as Plastibase (mineral oil gelled with polyethylene).

The effective amount of a compound of the present invention can bedetermined by one of ordinary skill in the art, and includes exemplarydosage amounts for a adult human of from about 0.001 to 100 mg/kg ofbody weight of active compound per day, preferably 0.01 to 1 mg/kg ofbody weight of active compound per day, that can be administered in asingle dose or in the form of individual divided doses, such as from 1to 4 times per day. In general, treatment regimens according to thepresent invention comprise administration to a human subject in need ofsuch treatment of from about 5 mg to about 1000 mg of the compound(s) ofthe present invention per day in single or multiple doses. It will beunderstood that the specific dose level and frequency of dosage for anyparticular subject can be varied and will depend upon a variety offactors including the activity of the specific compound employed, themetabolic stability and length of action of that compound, the species,age, body weight, general health, sex and diet of the subject, the modeand time of administration, rate of excretion, drug combination, andseverity of the particular condition. Preferred subjects for treatmentinclude animals, most preferably mammalian species such as humans, anddomestic animals such as dogs, cats and the like, subject tomotility-associated conditions.

The following examples serve to better illustrate, but not limit,preferred embodiments of the invention.

EXAMPLES General Experimental

The following examples represent preferred embodiments of the invention.All temperatures are in ° C. unless indicated otherwise.

The term LC refers to a Shimadzu high performance liquid chromatographyusing a 4 minute gradient of 0-100% solvent B [MeOH:H₂0:0.2% H₃PO₄] witha 1 min. hold, an ultra violet (uv) detector set at 220 nM and using acolumn (4.6×50 mm) packed with YMC C18 5 micron resin.

The term preparative LC refers to an automated Shimadzu system using theYMC ODS C18 5 micron preparative columns, and mixtures of solvent A (10%MeOH/90%H₂O/0.2% TFA) and solvent B (90% MeOH/10% H₂O/0.2% TFA).

To 50 mL of anhydrous THF were added benzodioxol-5-yl-methylamine (9.1g, 60.2 mmol) and hydrazinecarboxylic acid methyl ester (5.4 g, 60.0mrnol) followed by addition of carbonyldimidazole (9.7 g, 60.0 mmol),all at RT. The solution was stirred under N₂ overnight. The resultingsolid was filtered, washed with anhydrous THF and dried under vacuum togive a white solid 1A (10 g, 62%). LC=68% purity; Rt=2.00 min. LC-MSm/z=268 (M+H).

To 40 mL of 4N KOH aqueous solution was added 1A (10 g, ˜26 mmol), andstirred at 100° C. for 3 h. After cooling to RT, the solid was filteredoff, and aqueous filtrate was acidified with conc. HCl. The resultingprecipitate was filtered and dried under vacuum to give a pale-yellowsolid 1B (4.1 g, 58%). LC=95% purity; Rt=2.24 min. LC-MS m/z=135(M-triazolidinedione).

To a stirred solution of 4-(diethoxyphosphoryl)-butenoic acid ethylester (6.5 mL, 26.4 mmol) in 50 mL of anhydrous DMF was added sodiumhydride (1.17 g, 29.3 mmol, ˜60%) at 0° C. The reaction was stirred atRT for 30 min, followed by addition of 4-oxopiperidine-1-carboxylic acidtert-butyl ester (5.2 g, 26.1 mmol), and stirred for another 6 h at RT.The reaction was quenched with water, then diluted with EtOAc. Themixture was washed with water (5×), dried over Na₂SO₄, filtered andconcentrated. Purification by flash chromatography on silica gel (1:9EtOAc/hexanes as elutant) gave a white solid 1C (6.5 g, 84%). LC=99%purity; Rt=4.31 min. LC-MS m/z=318 (M+Na).

To a stirred solution of 1B (3.32 g, 14.1 mmol) in 35 mL of anhydrousDMF was added bis(trifluoroacetoxy)iodobenzene (6.07 g, 14.1 mmol) at 0°C., and the mixture was stirred at 0° C. for 2 h. A solution of 1C in 35ML anhydrous acetone was added at 0° C. to the above solution, and theresulting mixture was stirred at RT overnight. The reaction was quenchedwith water, then diluted with EtOAc. The mixture was washed with water(5×), dried over Na₂SO₄, filtered and concentrated. Purification byflash chromatography on silica gel (30-50% EtOAc/hexanes as elutant)gave a white foam solid 1D (3.46 g, 46%). LC 98% purity; Rt=4.12 min.LC-MS m/z=551 (M+Na).

To a stirred solution of 1D (3.46 g, 6.55 mmol) in a mixed solvent ofTHF (15 mL) and ethanol (7 mL) was added 13 mL of 1N NaOH at RT, andstirred at RT for 2 h. The solution was acidified with 1N HCl, thenconcentrated. It was extracted with EtOAc (3×), dried over Na₂SO₄,filtered and concentrated to give a light yellow foam solid 1E (3.4 g,100%). LC=97% purity; Rt=3.87 min. LC-MS m/z=501 (M+H).

To a stirred solution of 2-tert-butoxycarbonylamino-4-phenylbutyric acid(1.25 g, 4.5 mmol) in 10 mL DMF were added EDAC (1.7 g, 8.9 mmol) andHOAT (1.2 g, 8.8 mmol), and the resulting mixture was stirred at RT for3 h. An aqueous solution of saturated ammonium hydroxide (5.2 g, 44.5mmol, ˜30%) was added, and the mixture was stirred at RT overnight. Thereaction was diluted with EtOAc, washed with water (5×), 1N NaOH (3×),water again, dried over Na₂SO₄, filtered and concentrated. The resultingsolid was dissolved in 5 mL of dichloromethane followed by addition of10 mL of 20% TFA in dichloromethane, and the mixture was stirred at RTfor 2 hr. The compound was concentrated, redissolved in EtOAc, washedwith 1N NaOH, water, dried over Na₂SO₄, filtered and concentrated. Thecompound was redissolved in diethylether followed by addition of 0.5 mLof conc. HCl. It was concentrated to give a white foam solid 1F (680 mg,70%) as HCl salt. LC=85% purity; Rt=0.82 min. LC-MS m/z=179 (M+H).

To a stirred solution of 1E (2.7 g, 5.4 mmol) in 15 mL of methanol wasadded 270 mg of Pd/C catalyst under N₂. The reaction mixture was flushedseveral times with hydrogen gas, and stirred under a hydrogen gasballoon at RT overnight. The catalyst was filtered off, and filtrate wasconcentrated to give a white foam solid 1G (2.6 g, 96%). LC=94% purity;Rt=3.67 min. LC-MS m/z=503 (M+H).

To a stirred solution of 1G (1.7 g, 3.4 mmol) in a mixed solvent ofanhydrous toluene (10 mL) and methanol (6 mL) was added anazidotrimethylsilane solution (2.5 mL, 2M in toluene, 5 mmol), and themixture was stirred at RT overnight. The reaction mixture wasconcentrated, then diluted with water and EtOAc. The mixture was washedwith water (2×), dried over Na₂SO₄, filtered and concentrated.Purification by flash chromatography on silica gel (30-50% EtOAc/hexanesas elutant) gave a white foam solid 1H (1.7 g, 92%). LC=98% purity;Rt=3.78 min. LC-MS m/z=415 (M-Boc).

Compound 1H (1.7 g) was separated on a chiral preparative HPLC columnpacked with ChiralPak AS 2 μM (5×50 cm) using 10% absolute ethanol/90%hexanes as the solvents. The first eluting enantiomer was 1H-E1 (700 mg,99% ee) and the second eluting enantiomer was 1H-E2 (720 mg, 84% ee).

To a stirred solution of 1H-E1 (97 mg, 0.19 mmol) in 1 mL of methanolwas added 0.38 mL of 1N NaOH at RT, and stirred at RT for 2 h. Thesolution was acidified with 1N HCl, then concentrated. It was extractedwith EtOAc (3×), dried over Na₂SO₄, filtered and concentrated to give awhite foam solid 1G-E1 (88 mg, 94%). LC=98% purity; Rt=3.63 min. LC-MSm/z=503 (M+H).

To a stirred solution of 1G-E1 (50 mg, 0.1 mmol) in 0.5 mL of DMF wereadded PyAOP (52 mg, 0.1 mmol), 1F (24 mg, 0.11 mmol) and DIEA (35 μL,0.2 mmol) at RT, and stirred at RT overnight. The reaction was dilutedwith EtOAc, washed with water (2×), dried over Na₂SO₄, filtered andconcentrated. The intermediate was purified on a SCX column, packed with3 mg of resin functionalized with sulfonic acid. Removal ofBoc-protecting group was carried out with 2 mL of 30% TFA indichloromethane (v/v) at RT for 2 h. The TFA solution was concentratedand residue was purified on prepLC to give 30 mg (44%) of the titlecompound (Example 1) as a TFA salt. LC=97% purity, Rt=2.40 min, LC-MSm/z=563 (M+H); ¹H NMR (MeOH-d₄) δ 1.80-2.35 (m, 10H), 2.60-2.80 (m, 2H),3.10-3.30 (m, 3H), 3.48 (t, J=6 Hz, 1H), 4.30-4.40 (m, 2H), 4.53 (d, J=6Hz, 1H), 4.60 (d, J=6 Hz, 1H), 4.75-4.82 (m, 1H), 5.92 (s, 2H), 6.70 (d,J=9 Hz, 1H), 6.82-6.90 (m, 2H), 7.10-7.25 (m, 5H).

The compound was prepared according to the method described in Example 1from the reaction of 1E and L-Leucinamide hydrochloride followed byde-Boc. The initial mixtures were separated on prepLC, and the secondeluting isomer was the title compound (Example 2) as a TFA salt. LC=97%purity, Rt=2.40 min, LC-MS m/z=513 (M+H).

The compound was prepared according to the method described in Example 1from the reaction of 1E and L-Phenylalaninamide hydrochloride followedby de-Boc. The initial mixtures were separated on prepLC, and the secondeluting isomer was the title compound (Example 3) as a TFA salt. LC=95%purity, Rt=2.47 min, LC-MS m/z=547 (M+H).

1. A compound having the structure

or a pharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition comprising a compound as defined in claim 1 and apharmaceutically acceptable carrier therefor.
 3. A pharmaceuticalcombination comprising a compound as defined in claim 1 and anothertherapeutically active compound.
 4. The pharmaceutical combination asdefined in claim 3 wherein the other therapeutically active compound isa proton pump inhibitor, a histamine H2 receptor blocker, an antacid, agastrointestinal stimulant, a dopamine receptor blocker, a 5-HT4agonist, a 5-HT3 antagonist, an anti-anorexia agent, an agent for gallbladder stasis, an agent for treating postoperative paralytic ileus, anagent for treating scleroderma, an agent for treating intestinalpseudo-obstruction, an anti-gastritis agent, an anti-emesis agent, ananti-constipation agent, an agent for treating irritable bowel syndrome,an agent for treating functional dyspepsia, or an agent for treatingcolonic hypomotility.
 5. A method treating a disorder ofgastrointestinal motility, which comprises administering to a patient inneed of treatment a therapeutically effective amount of a compound ofthe structure

or a pharmaceutically acceptable salt thereof, a prodrug ester thereof,and all stereoisomers thereof; wherein R₁ is selected from alkyl, aryl,alkylaryl, cycloalkyl, alkenyl, alkynyl, arylalkyl, heteroaryl,heteroarylalkyl or heterocycloalkyl; Z is selected from —CON(R₄)R_(4a),—SO₂N(R₄)R_(4a), CN, and

R₄ and R_(4a) are the same or different and are independently selectedfrom hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl orheteroarylalkyl, or R₄ and R_(4a) can be joined together to form aheterocycle R_(4b) is selected from hydrogen, halogen, hydroxyl, CN,OCF₃, CF₃, CONH₂, SONH₂, SO₂CH₃, NHCOCH₃ or NHCO₂CH₃ and Q is asubstituted bicyclic heterocycle.
 6. The method as defined in claim 5where in the compound the substituted bicyclic heterocycle is selectedfrom

wherein r is 0, 1 or 2; and

represents a single bond or a double bond; and T is selected from alkyl,aryl, cycloalkyl, alkenyl, alkynyl, arylalkyl, heteroaryl,heteroarylalkyl and heterocycloalkyl, and where each of these groups maybe optionally substituted with R₅, R_(5a) and R_(5b); R₅, R_(5a) andR_(5b) are the same or different and are independently selected fromhydrogen, halogen, hydroxyl, OCF₃, CF₃, CN, NR₅C(R_(5d)),C(O)NR_(5c)(R_(5d)), OC(O)N(R_(5c))R_(5d), OR_(5c), SO₂R_(5c),SO₂N(R_(5c))R_(5d), alkyl, alkoxyl, aryl, arylalkyl, or heteroaryl; orR₅ and R_(5a) can be joined together with —OCH₂O— or —OCH₂CH₂O— to forma fused bicyclic ring with aryl or a heteroaryl group; R_(5c) and R_(5d)are the same or different and are independently selected from hydrogen,alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, orheterocycloalkyl or R_(5c) and R_(5d) can be joined together to form aheterocycle.
 7. The method as defined in claim 5 where in the compound Zis selected from —CON(R₄)R_(4a) and —SO₂N(R₄)R_(4a).
 8. The method asdefined in claim 5 where in the compound Z is CONH₂ and Q is


9. The method as defined in claim 5 wherein the compound has thestructure


10. The method as defined in claim 5 wherein the disorder ofgastrointestinal motility is gastroparesis, gastroesophageal refluxdisease, anorexia, gall bladder stasis, postoperative paralytic ileus,scleroderma, intestinal pseudoobstruction, gastritis, emesis, chronicconstipation (colonic inertia), irritable bowel syndrome, functionaldyspepsia, and colonic hypomotility.
 11. A method for treating adisorder of gastrointestinal motility, which comprises administering toa patient in need of treatment a therapeutically effective amount of apharmaceutical combination as defined in claim
 3. 12. The method asdefined in claim 11 wherein the disorder of gastrointestinal motility isgastroparesis, gastroesophageal reflux disease, anorexia, gall bladderstasis, postoperative paralytic ileus, scleroderma, intestinalpseudoobstruction, gastritis, emesis, chronic constipation (colonicinertia), irritable bowel syndrome, functional dyspepsia, and colonichypomotility.